Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter
Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter
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DOI：
10.1017/s1461145709000042
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发表时间：
2009-09-01
影响因子：
4.8
通讯作者：
Suhara, Tetsuya
中科院分区：
文献类型：
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作者：
Saijo, Takeaki;Maeda, Jun;Suhara, Tetsuya
使用正电子发射断层扫描 (PET) 对活体小动物中的神经传递成分进行可视化，有可能有助于神经活性药物的临床前开发，尽管候选化合物的定量动物 PET 数据是否可以外推到人类还有待检验。在这里，我们研究了大鼠 PET 研究中治疗药物对血清素转运蛋白 (5-HTT) 的占用率与我们从离体动物实验和临床 PET 扫描中获得的预定数据的可比性。大鼠接受不同剂量的氟伏沙明和新开发的化合物（2S）-1-[4-（3+二氯苯基）哌啶-1-基]-3-[2-（5-甲基-1,3,4-恶二唑-2-基）-苯并[b]呋喃-4-基氧基]丙-2-醇单盐酸盐（Wf-516）治疗，并接受PET扫描[C-11]3-氨基-4-(2-二甲氨基甲基-苯硫基)-苯甲腈 ([C-11]DASB)，一种用于 5-HTT 体内定量的选择性放射性配体。 PET 图像表明，[C-11]DASB 与 5-HTT 的结合减少，这是氟伏沙明和 Wf-516 剂量和/或血浆浓度的函数。使用 [C-11]DASB 的结合电位确定这些药物的半最大效应剂量（分别为 15.2 mg/kg 和 3.1 mg/kg）与我们之前在大鼠中的离体测量估计的剂量（分别为 4.5 mg/kg 和 1.1 mg/kg）相当，因为这些结果之间仅存在 3 倍的差异。此外，中枢 5-HTT 占据 50% 所需的氟伏沙明血浆浓度 (6.1 ng/ml) 几乎相当于人类 PET 研究中确定的值 (4.6 ng/ml)。这些发现支持这样的观点，即小动物 PET 和 [C-11]DASB 的联合使用有助于对正在开发的针对 5-HTT 的药物与已建立的抑制剂进行定量比较，并预测性估计它们在人类中发挥治疗作用的血浆浓度。
Visualization of neurotransmission components in living small animals using positron emission tomography (PET) has the potential of contributing to the preclinical development of neuroactive drugs, although it is yet to be examined whether quantitative animal PET data on candidate compounds can be extrapolated to humans. Here, we investigated the comparability of the occupancies of serotonin transporter (5-HTT) by therapeutic agents in rat PET studies with our predetermined data from ex-vivo animal experiments and clinical PET scans. Rats were treated with varying doses of fluvoxamine and a newly developed compound, (2S)-1-[4-(3+dichlorophenyl) piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride (Wf-516), and underwent PET scans with [C-11]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile([C-11]DASB), a selective radioligand for in-vivo quantification of 5-HTT. PET images indicated a reduction of [C-11]DASB binding to 5-HTT as a function of the doses and/or plasma concentrations of fluvoxamine and Wf-516. The doses of these drugs at half-maximal effect (15.2 mg/kg and 3.1 mg/kg, respectively), determined that using binding potentials for [C-11]DASB, were comparable to those estimated by our previous ex-vivo measurements in rats (4.5 mg/kg and 1.1 mg/kg, respectively), as there was only a 3-fold difference between these results. Moreover, the plasma concentration of fluvoxamine needed for 50% occupancy of central 5-HTT (6.1 ng/ml) was almost equivalent to the value determined in human PET studies (4.6 ng/ml). These findings support the view that the conjunctive use of small-animal PET and [C-11]DASB facilitates a quantitative comparison of in-development drugs targeting 5-HTT with established inhibitors and a predictive estimation of their plasma concentrations exerting therapeutic effects in humans.